The present invention relates to a novel di- or trifluoromethanesulfonyl anilide derivative or a salt thereof; a process for production thereof; a herbicide containing said derivative or salt as an active ingredient; and novel raw material compounds used in said process.
It is known that N-fluoromethanesulfonyl anilide derivatives having a pyrimidinyl-containing group at the 2-position, for example, an N-trifluoromethanesulfonyl anilide derivative of 2-pyrimidinylmethyl-substituted or 2-pyrimidinyloxy or thioxy-substituted aniline has a herbicidal activity (see National Publication of International Patent Application No. 7-501053 and WO 93/09099).
It is also known that an N-trifluoromethanesulfonyl anilide derivative of 2-pyrimidinylhydroxymethyl-substituted aniline has a plant growth-regulating activity (see WO 96/41799).
However, it is not yet known that any of N-di- or trifluoromethanesulfonyl derivatives of aniline having a pyrimidinyl-containing group at the 2-position has a herbicidal activity.
In the cultivation of paddy rice, it has been an important task in recent years to control noxious weeds which emerge in paddy field and which are difficult to control effectively with conventional herbicides, i.e. difficult-to-control weeds. These weeds emerge over a long period of time and, therefore, need to be controlled over a long period of time. Gramineous weeds (other than rice plant) belonging to the same family as rice plant belongs to, for example, Echinochloa oryzicola Vasing., etc. emerge over a long period of time as well and grow actively and rapidly; therefore, their control is important as well. No herbicide is developed currently which has a high activity to the above weeds and can control them. Hence, it is desired to develop a chemical agent which has a high herbicidal activity not only to difficult-to-control weeds but also to gramineous weeds, which can control a wide variety of weeds emerging in paddy field, over a long period of time, and which is highly safe to mammals.
Under the above situation, the present invention aims at providing a novel compound which is effective for the removal of a wide variety of weeds including difficult-to-control weeds, emerging in paddy field and which is safe to mammals; a process for production thereof; a herbicide containing the compound as an active ingredient; and novel raw material compounds used in said process.
The present inventors made an intensive study to develop a novel compound having a herbicidal activity. As a result, the present inventors found out that an N-di- or a trifluoromethanesulfonyl derivative of 2-pyrimidinylhydroxymethyl-substituted aniline has a herbicidal activity to a wide variety of weeds at a low dosage, is very effective particularly to gramineous weeds and, moreover, is highly safe to mammals. The present invention has been completed based on the above finding.
The present invention provides a di-, or trifluoromethanesulfonyl anilide derivative represented by the following general formula (I): 
(wherein R1 is a hydrogen atom, an alkyl group or an alkoxyalkyl group; and R2 is a hydrogen atom when R1 is a hydrogen atom or an alkyl group, and is a hydrogen atom or a fluorine atom when R1 is an alkoxyalkyl group), or a salt thereof, both of said derivative and said salt having a herbicidal activity.
Each of the compounds represented by the general formula (I) can be produced, for example, by reacting a 2-substituted aniline derivative (II) with a di- or trifluoromethanesulfonyl halide or trifluoromethanesulfonic-acid anhydride according to the following reaction formula (1): 
(wherein X is a halogen atom, and R1 and R2 each have the same definition as given above), or by reducing a 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-N-di- or trifluoromethanesulfonyl anilide derivative (III) according to the following reaction formula (2): 
(wherein R1 and R2 each have the same definition as given above).
The compounds represented by the general formula (II) or (III), used in the above production processes are also novel compounds not described in any literature.
In the present compound represented by the general formula (I), R1 is a hydrogen atom, an alkyl group or an alkoxyalkyl group. The alkyl group is preferably a straight chain or branched chain alkyl group having 1 to 5 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tertbutyl group, n-pentyl group, 1-methylbutyl group, n-hexyl group or the like. The alkoxyalkyl group is preferably a straight chain or branched chain alkoxyalkyl group having 2 to 6 carbon atoms, such as methoxymethyl group, methoxyethyl group, ethoxyethyl group, 3-ethoxypropyl group, 1-methyl-3-methoxybutyl group or the like.
In the present compound represented by the general formula (I), R2 is a hydrogen atom when R1 is a hydrogen atom or an alkyl group, and is a hydrogen atom or a fluorine atom when R1 is an alkoxyalkyl group. When R2 is a hydrogen atom, the present compound represented by the general formula (I) is a difluoromethanesulfonyl anilide derivative; when R2 is a fluorine atom, the present compound represented by the general formula (I) is a trifluoromethanesulfonyl anilide derivative.
The salt of the compound represented by the general formula (I) is a salt between the sulfonylamide group moiety of the compound and a base. As the base, there can be mentioned a sodium salt and a potassium salt.
As the representative examples of the di- or trifluoromethanesulfonyl anilide derivative represented by the general formula (I), there can be mentioned 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-methoxymethyl-N-difluoromethanesulfonyl anilide, 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-methoxyethyl-N-difluoromethanesulfonyl anilide, 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-ethoxymethyl-N-difluoromethanesulfonyl anilide, 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-N-difluoromethanesulfonyl anilide, 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-ethyl-N-difluoromethaesulfonyl anilide, 2-[( 4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-methoxymethyl-N-trifluoromethanesulfonyl anilide, 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-methoxyethyl-N-trifluoromethanesulfonyl anilide, and 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-ethoxymethyl-N-trifluoromethanesulfonyl anilide.
The compound represented by the general formula (I) can be produced, for example, by reacting a 2-substituted aniline derivative represented by the general formula (II) with a di- or trifluoromethanesulfonyl halide or trifluoromethanesulfonic acid anhydride according to the above-shown reaction formula (1), or by reducing a 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-N-di- or trifluoromethanesulfonyl anilide derivative represented by the general formula (III) according to the above-shown reaction formula (2).
The former process is conducted ordinarily in the presence of a base in an inert solvent such as aliphatic or alicyclic hydrocarbon (e.g. pentane, hexane or cyclohexane), aromatic hydrocarbon (e.g. toluene or xylene), halogenated hydrocarbon (e.g. dichloromethane or chloroform), ether (e.g. diethyl ether, tetrahydrofuran or 1,4-dioxane), ester (e.g. methyl acetate or ethyl acetate), nitrile (e.g. acetonitrile or propionitrile), aprotic polar solvent (e.g. N,N-dimethylformamide, N,N-dimethyl sulfoxide or sulfolane) or mixture thereof.
The base used above is a base conventionally used in a reaction between aniline and acid halide, such as alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide), alkaline earth metal hydroxide (e.g. calcium hydroxide) or organic base (e.g. trimethylamine, triethylamine, N,N-dimethylaniline or pyridine).
The reaction temperature is selected in a range of xe2x88x9270 to 250xc2x0 C., preferably xe2x88x9270 to 40xc2x0 C. The reaction time differs depending upon the kinds of raw material compounds used, the reaction temperature used, etc. but is about 5 minutes to 7 days.
The latter process is conducted ordinarily in an inert solvent such as alcohol (e.g. methanol or ethanol), ether (e.g. diethyl ether, tetrahydrofuran or 1,4-dioxane), ester (e.g. methyl acetate or ethyl acetate), nitrile (e.g. acetonitrile or propionitrile), aprotic polar solvent (e.g. N,N-dimethylformamide, N,N-dimethyl sulfoxide or sulfolane) or mixture thereof.
The reduction is conducted in the presence of a reducing agent, for example, an alkali metal-hydrogen complex compound (e.g. sodium boron hydride) at a temperature ranging from xe2x88x9270xc2x0 C. to the boiling point of the solvent used, preferably xe2x88x9220 to 40xc2x0 C. The reaction time differs depending upon the kinds of the raw material compounds used, the reaction temperature used, etc. but is about 5 minutes to 7 days.
The compounds of the general formula (II) or (III) used as a raw material in the above production processes are as well novel compounds not described in any literature.
These compounds can be easily produced from corresponding 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile (IV) according to the following reaction scheme in accordance with the production process described in, for example, J. Agr. Food. Chem., Vol. 22, No. 6, p. 1111 (1974); J. Chem. Researchers, 1977, p. 186; or Heterocycles, Vol. 38, No. 1, p. 125. 
(wherein R1, R2 and X each have the same definition as given above).
The compound of the general formula (II) can be produced, for example, as follows. A 2-nitrophenylacetonitrile derivative is reacted with a 2-halogeno- or alkylsulfonyl-4,6-dimethoxypyrimidine in the presence of a base, or a 2-halogeno-nitrobenzene derivative is reacted with 2-(4,6-dimethoxypyrimidine-2-yl)acetonitrile in the presence of a base, to obtain 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile (IV). The compound (IV) is subjected to oxidative decyanation to obtain a compound of the general formula (V). The nitro group of the compound (V) is reduced to convert it into an amino group to obtain a compound of the general formula (VI). The carbonyl group of the compound (VI) is reduced to a hydroxymethyl group to obtain a compound of the general formula (II).
The oxidative decyanation for converting the compound of the general formula (IV) into the compound of the general formula (V) is conducted by, in a first step, oxidation with an oxidizing agent and, in a second step, treatment with a base.
This reaction is conducted ordinarily in an inert solvent such as aliphatic or alicyclic hydrocarbon (e.g. pentane, hexane or cyclohexane), aromatic hydrocarbon (e.g. toluene or xylene), halogenated hydrocarbon (e.g. dichloromethane or chloroform), ether (e.g. diethyl ether, tetrahydrofuran or 1,4-dioxane), ketone (e.g. acetone or methyl ethyl ketone), ester (e.g. methyl acetate or ethyl acetate), nitrile (e.g. acetonitrile or propionitrile), aprotic polar solvent (e.g. N,N-dimethylformamide, N,N-dimethyl sulfoxide or sulfolane), water, or mixture thereof.
As the oxidizing agent used in the first step, there can be mentioned, for example, organic peracids such as m-chloroperbenzoic acid and the like.
The base used in the second step can freely be selected from the bases conventionally used in the oxidative decyanation of this kind. Such bases include, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as calcium hydroxide and the like; and organic bases such as trimethylamine, triethylamine, N,N-dimethylaniline, pyridine and the like.
The temperature employed in the above reaction is selected in a range of xe2x88x9270 to 250xc2x0 C., preferably xe2x88x9220 to 40xc2x0 C. The reaction time differs depending upon the kinds of the oxidizing agent and base used and the reaction temperature employed, but is ordinarily 5 minutes to 7 days.
The reaction for reducing the nitro group of the compound of the general formula (V) to convert it into an amino group to obtain the aniline derivative of the general formula (VI) can be conducted with a reducing agent in the presence of a catalyst in an inert solvent.
The inert solvent includes, for example, alcohols such as methanol, ethanol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile, propionitrile and the like; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethyl sulfoxide, sulfolane and the like; water; and mixed solvents thereof.
As the reducing agent, there are used, for example, metals such as iron, zinc and tin. As the catalyst, there are used, for example, organic acids such as acetic acid.
The above reaction is conducted at a temperature in a range of ordinarily 20xc2x0 C. to the boiling point of the solvent used. The reaction time differs depending upon the reducing agent, catalyst and reaction temperature used, but is ordinarily 5 minutes to 7 days.
The reduction for converting the carbonyl group of the compound of the general formula (VI) obtained above, into a hydroxymethyl group can be conducted in the same manner as used in the above-mentioned reduction of the compound of the general formula (III) for production of the present compound (I).
Meanwhile, the compound of the general formula (III) can be produced, for example, by reducing the nitro group of 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile (IV) to convert it into an amino group to obtain a compound of the general formula (VII), then reacting the compound (VII) with di- or trifluoromethanesulfonyl halide or trifluoromethanesulfonic acid anhydride in the presence of a base to produce an indole compound of the general formula (VIII), and subjecting the indole compound (VIII) to oxidation for ring opening.
The reaction for reducing the nitro group of the compound of the general formula (IV) to convert it into an amino group is conducted by hydrogenation in the presence of a catalyst in an inert solvent. The inert solvent can be the same solvent as used in production of the compound of the general formula (V). The catalyst can freely be selected from those conventionally used in catalytic reduction, such as platinum palladium, palladium carbon and the like.
The reaction of the compound of the general formula (VII) with the di- or trifluoromethanesulfonyl halide or trifluoromethanesulfonic acid anhydride can be conducted in the same manner as in the above-mentioned reaction of the compound of the general formula (II) with the di- or trifluoromethanesulfonyl halide or trifluoromethanesulfonic acid anhydride for production of the present compound (I).
The reaction for subjecting the indole derivative of the general formula (VIII) to oxidation for ring opening is conducted by, in first step, treatment of the compound with an oxidizing agent and, in second step, treatment with a base.
This reaction is conducted ordinarily in an inert solvent such as aliphatic or alicyclic hydrocarbon (e.g. pentane, hexane or cyclohexane), aromatic hydrocarbon (e.g. toluene or xylene), halogenated hydrocarbon (e.g. dichloromethane or chloroform), ether (e.g. diethyl ether, tetrahydrofuran or 1,4-dioxane), ketone (e.g. acetone or methyl ethyl ketone), ester (e.g. methyl acetate or ethyl acetate), nitrile (e.g. acetonitrile or propionitrile), aprotic polar solvent (e.g. N,N-dimethylformamide, N,N-dimethyl sulfoxide or sulfolane), water, or mixture thereof.
As the oxidizing agent, there can be mentioned, for example, organic peracids such as m-chloroperbenzoic acid and the like.
As the base, there are used those conventionally used in the reaction of this kind, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as calcium hydroxide and the like; and organic bases such as trimethylamine, triethylamine, N,N-dimethylaniline, pyridine and the like.
The reaction temperature is selected in a range of xe2x88x9270 to 250xc2x0 C., preferably xe2x88x9220 to 40xc2x0 C. The reaction time differs depending upon the base and reaction temperature used, but is ordinarily 5 minutes to 7 days.
The herbicide containing the compound represented by the general formula (I) as an active ingredient can be formulated in various forms conventionally used in general herbicides, such as dust, water dispersible powder, emulsifiable concentrate, fine granules, granules and the like. The compound (I) itself may be used as a herbicide.
The vehicle and additives used in formulation of the above herbicide can freely be selected from those ordinarily used in herbicide formulation, depending upon the application purpose of the herbicide formulated.
As the carrier used in formulation of the above herbicide, there can be mentioned, for example, solid carriers such as talc, bentonite, clay, kaolin, diatomaceous earth, white carbon, vermiculite, calcium carbonate, slake lime, silica sand, ammonium sulfate, urea and the like; and liquid carriers such as isopropyl alcohol, xylene, cyclohexane, methylnaphthalene and the like.
As the surfactant or the dispersant, there can be mentioned, for example, metal alkylbenzenesulfonates, metal dinaphthylmethanedisulfonates, alkyl sulfate salts, alkylarylsulfonic acid salt-formalin condensates, ligninsulfonic acid salts, polyoxyethylene glycol ether, polyoxyethylene alkyl aryl ether and polyoxyethylene sorbitan monoalkylates.
As the auxiliary agent, there can be mentioned, for example, carboxymethyl cellulose, polyethylene glycol and gum arabic.
The herbicide is applied by diluting it in an appropriate concentration and spraying the resulting material, or is applied directly.
The herbicide of the present invention is applied to foliage, soil, water surface, etc.
The amount of the active ingredient in the present herbicide is appropriately determined depending upon the application purpose of the herbicide, but can be selected in a range of 0.01 to 10% by weight, preferably 0.05 to 5% by weight when the herbicide is a dust or granules, and in a range of 1 to 50% by weight, preferably 5 to 30% by weight when the herbicide is an emulsifiable concentrate or a water dispersible powder.
The application amount of the present herbicide differs depending upon the kind of the compound contained in the herbicide, the weed(s) to be removed, the mode of emergence of weed(s), the environmental conditions, the type of the herbicide formulation, etc. However, the amount can be selected in a range of 0.1 g to 5 kg, preferably 1 g to 1 kg per 10 ares in terms of the amount of active ingredient when the herbicide is, for example, a dust or granules and is used directly. When the herbicide is, for example, an emulsifiable concentrate or a water dispersible powder and is used in a liquid form, the amount of active ingredient can be selected in a range of 0.1 to 50,000 ppm, preferably 10 to 10,000 ppm.
The herbicide of the present invention may as necessary be used in combination with an insecticide, a fungicide, other herbicide, a plant growth regulator, a fertilizer, etc.
Next, the present invention is described in more detail below by way of Examples. However, the present invention is in no way restricted by these Examples.
(1) 50 g (0.31 M) of 2-(2-nitrophenyl)acetonitrile was dissolved in 500 ml of dimethylformamide. Thereto was added 24.7 g (0.62 M) of 60% sodium hydride. The mixture was stirred at room temperature for 2 hours. Then, 68 g (0.31 M) of 4,6-dimethoxy-2-methanesulfonylpyrimidine was added. The mixture was stirred at 80xc2x0 C. for 1 hour to give rise to a reaction. The reaction mixture was poured into water, followed by neutralization with dilute hydrochloric acid. The mixture was subjected to extraction with ethyl acetate. The extract was washed with water, dried and subjected to vacuum distillation to remove the solvent. The residue was recrystallized from ethanol to obtain 73.3 g (yield: 79%) of 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile as a white powder (melting point: 88 to 89xc2x0 C.).
Data obtained
1H-NMR 60 MHz CDCl3 TMS 7.5-8.2 (m, 4H), 6.4 (s, 1H), 5.9 (s, 1H), 3.8 (s, 6H)
(2) 3.0 g (10 mM) of the 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile obtained in the above (1) and 0.3 g of 10% palladium carbon were suspended in 100 ml of methanol. While the suspension was stirred at room temperature overnight, hydrogen was added thereto. The solid was removed by filtration. The filtrate was subjected to vacuum distillation to remove methanol. The residue was subjected to silica gel column chromatography (elutant solvent: ethyl acetate/hexane=1/1) for purification to obtain 1.8 g (yield: 67%) of 2-(2-aminophenyl)-2-(4,6-dimethoxypyrimidine-2-yl)acetonitrile as a light yellow candy-like substance.
Data obtained
1H-NMR 60 MHz CDCl3 TMS 6.5-7.6 (m, 4H), 6.9 (s, 1H), 5.3 (s, 1H), 4.6 (br, 2H), 3.9 (s, 6H)
(3) In 100 ml of chloroform were dissolved 4.0 g (14.8 mM) of the 2-(2-aminophenyl)-2-(4,6-dimethoxypyrimidine-2-yl)acetonitrile obtained in the above (2), 2.5 g (31.6 mM) of pyridine and 2.8 g (18.6 mM) of difluoromethanesulfonyl chloride. The solution was stirred at room temperature overnight. The reaction mixture was washed with dilute hydrochloric acid and a saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate. The resulting mixture was subjected to vacuum distillation to remove the solvent. The residue was subjected to silica gel column chromatography (elutant solvent: ethyl acetate/hexane=1/3) for separation and purification to obtain 2.0 g (yield: 35%) of 2-amino-1-difluoromethanesulfonyl-3-(4,6-dimethoxypyrimidine-2-yl)indole as a light yellow powder (melting point: 156 to 158xc2x0 C.).
Data obtained
1H-NMR 300 MHz CDCl3 TMS 8,57 (d, 1H), 7.81 (d, 1H), 7.56 (br, 2H), 7.34 (t, 1H), 7.15 (t, 1H), 6.43 (t, 1H), 5.84 (s, 1H), 4.05 (s, 6H)
(4) In 30 ml of chloroform were dissolved 2.0 g (5.2 mM) of the 2-amino-1-difluoromethanesulfonyl-3-(4,6-dimethoxypyrimidine-2-yl)indole obtained in the above (3) and 2.0 g (5.8 mM) of 50% m-chloroperbenzoic acid. The solution was stirred at room temperature for 12 hours. Then, 15 ml of a 10% aqueous sodium hydroxide solution was added. The mixture was stirred at room temperature for 1 hour. 50 ml of chloroform was added. The organic layer was washed with 5% dilute hydrochloric acid and a saturated aqueous sodium chloride solution, followed by drying. The resulting solution was subjected to vacuum distillation to remove the solvent. The residue was subjected to silica gel column chromatography (elutant solvent: ethyl acetatein-hexane=1/5) for purification to obtain 1.0 g (yield: 52%) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-N-difluoromethanesulfonyl anilide as a white powder (melting point: 131 to 133xc2x0 C.).
Data obtained
1H-NMR 300 MHz CDCl3 TMS 11.36 (br, 1H), 7.86 (d, 1H), 7.70 (d, 1H), 7.62 (t, 1H), 7.18 (t, 1H), 6.35 (t, 1H), 6.19 (s, 1H), 3.97 (s, 6H)
(1) 11.2 g (0.28 M) of 60% sodium hydride was suspended in 100 ml of N,N-dimethylformamide. While the suspension was cooled to 10xc2x0 C. or lower in an ice water bath and stirred, thereto was dropwise added a solution of 25 g (0.14 M) of 2-(4,6-dimethoxypyrimidine-2-yl)acetonitrile dissolved in 100 ml of N,N-dimethylformamide. After the completion of the dropwise addition, the mixture was stirred at room temperature until there was no evolution of hydrogen. While the mixture was cooled to 10xc2x0 C. or lower in an ice water bath and stirred, thereto was dropwise added a solution of 28 g (0.14 M) of 2-chloro-6-methoxymethylnitrobenzene dissolved in 100 ml of dimethylformamide. Then, the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water. The mixture was acidified with 10% hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and water, dried and concentrated under reduced pressure. The resulting crystals were washed with a mixed solvent of ethanol and isopropyl ether to obtain 31 g (yield: 64%) of 2-(4,6-dimethoxypyrimidine-2-yl)-2-(3-methoxymethyl-2-nitrophenyl)acetonitrile as a reddish brown powder (melting point: 112 to 113xc2x0 C).
Data obtained
1H-NMR 300 MHz CDCl3 TMS 7.83 (m, 1H), 7.58 (m, 2H), 5.91 (s, 1H), 5.72 (s, 1H), 4.53 (s, 2H), 3.90 (s, 6H), 3.39 (s, 3H)
(2) 11.2 g (0.28 M) of 60% sodium hydride was suspended in 100 ml of N,N-dimethylformamide. While the suspension was cooled to 10xc2x0 C. or lower in an ice water bath and stirred, there-to was dropwise added a solution of 29 g (0.14 M) of 3-methoxymethyl-2-nitrophenylacetonitrile dissolved in 100 ml of N,N-dimethylformamide. After the completion of the dropwise addition, the mixture was stirred at room temperature until there was no evolution of hydrogen. While the mixture was cooled to 10xc2x0 C. or lower in an ice water bath and stirred, thereto was added 30 g (0.14 M) of 4,6-dimethoxy-2-methylsulfonylpyrimidine. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water. The mixture was acidified with 10% hydrochloric acid. The resulting crude crystals were collected by filtration, washed with water and a mixed solvent of ethanol and isopropyl ether to obtain 42 g (yield: 87%) of 2-(4,6-dimethoxypyrimidine-2-yl)-2-(3-methoxymethyl-2-nitrophenyl)acetonitrile as a reddish brown powder (melting point: 112 to 113xc2x0 C.).
Data obtained
1H-NMR 300 MHz CDCl3 TMS 7.83 (m, 1H), 7.58 (m, 2H), 5.91 (s, 1H), 5.72 (s, 1H), 4.53 (s, 2H), 3.90 (s, 6H), 3.39 (s, 3H)
(3) In 30 ml of chloroform were dissolved 3.5 g (10 mM) of the 2-(4,6-dimethoxypyrimidine-2-yl)-2-(3-methoxymethyl-2-nitrophenyl)acetonitrile obtained in the above (1) or (2) and 6.0 (17 mM) of 50% m-chloroperbenzoic acid. The solution was stirred at room temperature for 12 hours. Thereto was added 15 ml of a 10% aqueous sodium hydroxide solution, followed by stirring at room temperature for 1 hour. 50 ml of chloroform was added. The organic layer was washed with 5% dilute hydrochloric acid and a saturated aqueous sodium chloride solution, dried, and subjected to vacuum distillation to remove the solvent. The residual crystals were washed with ethanol-diisopropyl ether to obtain 2.8 g (yield: 84%) of (4,6-dimethoxypyrimidine-2-yl)-3-methoxymethyl-2-nitrophenylketone as a white powder (melting point: 111 to 113xc2x0 C.).
Data obtained
1H-NMR 300 MHz CDCl3 TMS 7.90 (d, 1H), 7.72 (t, 1H), 7.61 (d, 1H), 6.13 (s, 1H), 4.78 (s, 2H), 3.90 (s, 6H), 3.47 (s, 3H)
(4) 3.3 g (10 mM) of the (4,6-dimethoxypyrimidine-2-yl)-3-methoxymethyl-2-nitrophenylketone obtained in the above (3), 3 g (54 mM) of an iron powder, 20 ml of water and a mixture of 150 ml of ethyl acetate and 1 ml of acetic acid were subjected to a reaction at 50xc2x0 C. for 5 hours. The insolubles in the reaction mixture were separated by filtration using a filter aid. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and subjected to vacuum distillation to remove the solvent. The residual crystals were washed with diisopropyl ether to obtain 2.4 g (yield: 80%) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-methoxymethylaniline as yellow crystals (melting point: 100 to 101xc2x0 C.).
Data obtained
1H-NMR 300 MHz CDCl3 TMS 7.37 (d, 1H), 7.24 (d, 1H), 7.14 (br, 2H), 6.53 (t, 1H), 6.11 (s, 1H), 4.55 (s, 2H), 0.96 (s, 6H), 3.35 (S, 3H)
(5) 3.1 g (10 mM) of the 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-methoxymethylaniline obtained in the above (4) was dissolved in 50 ml of a 1:1 (by volume ratio) mixed solvent of tetrahydrofuran and water. While the solution was stirred at room temperature, thereto was added 0.6 g (16 mM) of sodium boron hydride. The mixture was stirred at room temperature for 2 hours. 50 ml of ice water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and subjected to vacuum distillation to remove the solvent. The residual crystals were washed with diisopropyl ether to obtain 2.8 g (yield: 92%) of 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-methoxymethylaniline as a white powder (melting point: 40 to 42xc2x0 C.).
Data obtained
1H-NMR 300 MHZ CDCl3 TMS 7.30 (d, 1H), 7.01 (d, 1H), 6.73 (t, 1H), 5.93 (s, 1H), 5.84 (d, 1H), 5.17 (br, 2H), 4.68 (d, 1H), 4.51 (q, 2H), 3.94 (s, 6H), 3.32 (s, 3H)
(1) The operation of (1) of Reference Example 2 was repeated except that the 2-chloro-6-methoxymethylnitrobenzene used in (1) of Reference Example 2 was replaced by 2-ethyl-6-fluoronitrobenzene, whereby was obtained 2-(4,6-dimethoxypyrimidine-2-yl)-2-(3-ethyl-2-nitrophenyl)acetonitrile as a liver brown powder (melting point: 113 to 114xc2x0 C.). The yield was 66.6%.
Data obtained
1H-NMR 300 MHz CDCl3 TMS 7.73 (d, 1H), 7.50 (t, 1H), 7.36 (d, 1H), 5.92 (s, 1H), 5.52 (s, 1H), 3.91 (s, 6H), 2.56 to 2.76 (m, 2H), 1.26 (t, 3H)
(2) The 2-(4,6-dimethoxypyrimidine-2-yl)-2-(3-ethyl-2-nitrophenyl)acetonitrile obtained in the above (1) was subjected to the same treatment as in (3) of Reference Example 2, whereby was obtained (4,6-dimethoxypyrimidine-2-yl)-3-ethyl-2-nitrophenyl ketone as a white powder (melting point: 116 to 117xc2x0 C.). The yield was 100%.
Data obtained
1H-NMR 300 MHz CDCl3 TMS 7.51 to 7.63 (m, 3H), 6.13 (s, 1H), 3.92 (s, 6H), 2.88 (q, 2H), 1.32 (t, 3H)
(3) The (4,6-dimethoxypyrimidine-2-yl)-3-ethyl-2-nitrophe nylketone obtained in the above (2) was subjected to the same treatment as in (4) of Reference Example 2, whereby was obtained 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethylaniline as a yellow powder (melting point: 122 to 123xc2x0 C.). The yield was 64%.
Data obtained
1H-NMR 300 MHz CDCl3 TMS 7.25 (d, 2H), 6.67 (br, 2H), 6.56 (t, 1H), 6.11 (s, 1H), 3.95 (s, 6H), 2.56 (q, 2H), 1.30 (t, 3H)
(4) The 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethylaniline obtained in the above (3) was subjected to the same treatment as in (5) of Reference Example 2, whereby was obtained 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-ethylaniline as a white powder (melting point: 85 to 86xc2x0 C.). The yield was 93.7%.
Data obtained
1H-NMR 300 MHz CDCl3 TMS 7.19 (d, 1H), 7.03 (d, 1H), 6.76 (t, 1H), 5.93 (s, 1H), 5.87 (d, 1H), 4.71 (br, 2H), 4.69 (d, 1H), 3.93 (s, 6H), 2.56 (q, 2H), 1.25 (t, 3H)